During the past year The Molecular Hematology Laboratory has continued to assist clinicians in exploring the impact of novel approaches to conditioning, graft selection, and immunosuppression on myeloid and T cell engraftment after allogeneic stem cell transplantation. Intramural scientists from NCI and NIAID have demonstrated the usefulness of allogeneic stem cell transplants in treating patients with a number of hereditary immunodeficiency and myelodysplastic syndromes, particularly the newly described monomac syndrome now linked to mutations in the DNA transcription factor GATA2. To date, more than 10 patients have received allotransplants at the NIH for this syndrome with only one early death, and successful engraftment in each of the other 10. In most cases, the patients have done well with immune and hematologic reconstitution. During the past year 2 patients of this cohort have developed late clonal myeloid disorders. Case 1 developed a relapse in her underlying myelodysplastic syndrome 1.5 years post transplant. This was successfully treated by ablative conditioning and a second stem cell transplant. Case 2 developed MDS/acute myelogenous leukemia two years post transplant. Surprisingly, despite the presence of myelodysplasia in the host before transplantation, chimerism and cytogenetic studies indicate the malignancy arose de novo from the cord blood stem cells used for hematopoietic reconstitution and not from recurrent host disease. In light of these findings, careful monitoring of hematologic and chimerism status of these patients must be continued. Investigators from NIDDK, have now performed non-myeloablative stem cell transplants in over 30 patients with hemoglobinopathies. Using conditions which promote split chimerism i.e. extensive myeloid and minimal T cell donor engraftment, to date these investigators have experienced only a few instances of graft failure with little graft versus host disease and no direct treatment related mortality. This program continues to follow previously transplanted patients and has performed 4 new transplants in the past 12 months. Investigators from NHLBI, continues their innovative protocol for treating patients with severe aplastic anemia with a combination transplant containing T-cell depleted, haploidentical myeloid cells and matched unselected cord blood cells from an unrelated donor. To date, this group has transplanted more than 10 patients in this manner with excellent results. Multidonor chimerism studies document a very dynamic pattern of engraftment. In many instances, haploidentical myeloid cells and cord derived T cells dominate during early engraftment, and cord derived cells later replace haploidentical cells in the myeloid compartment. On occasion the pattern of engraftment is more variable, but to date only one of 14 patients has developed a graft failure and prolonged cytopenias are uncommon. This protocol has demonstrated the feasibility of using a mixture of haploidentical bone marrow cells and cord blood derived cells place of two cords, as a source of donor cells for allotransplantation in adolescents and adults without a good related or unrelated donor match.